Genetic Basis of Common Human Disease: Insight into the Role of Missense SNPs from Genome-Wide Association Studies

Abstract

Recent genome wide association studies have led to the reliable identification of SNPs at a number of loci associated with increased risk of specific common human diseases. Each such locus implicates multiple possible candidate SNPs for involvement in disease mechanism. A variety of mechanisms may link the presence of a SNP to altered in vivo gene product function and hence contribute to disease risk. Here we report an analysis of the role of one of these mechanisms, missense SNPs (msSNPs) in proteins in seven complex trait diseases. Linkage disequilibrium information was used to identify possible candidate msSNPs associated with increased disease risk at each of 356 loci for the seven diseases. Two computational methods were used to estimate which of these SNPs has a significant impact on in vivo protein function. 69% of the loci have at least one candidate msSNP and 33% have at least one predicted high impact msSNP. In some cases, these SNPs are in well-established disease related proteins, such as MST1 (macrophage stimulating 1) for Crohn’s disease, In others, they are in proteins identified by GWAS as likely candidates for disease relevance, but previously without known mechanism, such as ADAMTS13 (ADAM metallopeptidase with thrombospondin type 1 motif, 13) for Coronary Artery Disease. In still other cases, the missense SNPs are in proteins not previously suggested as disease candidates, such as TUBB1 (tubulin, beta 1, class VI) for Hypertension. Together, these data support a substantial role for this class of SNPs in susceptibility to common human disease.

Gene polymorphism linked to increased asthma and IBD risk alters gasdermin-B structure, a sulfatide and phosphoinositide binding protein

“…Of the human genomes sequenced by the 1000 Genomes Project (33), the GSDMB polymorphisms encoding the alleles containing either Gly299:Pro306 or Arg299:Ser306 are present at ∼50% frequency in the general population (22). The GSDMB SNPs associated with inflammatory disease risks encode the Arg299:Ser306 variant.…”

“…This study examined the "canonical" GSDMB isoform 1 [411 residues, Q8TAX9-1, identified in National Center for Biotechnology Information (NCBI) as GSDML and GSDMB isoform X3]. Analyses of GWAS data by Pal and Moult identified two GSDMB SNPs (dbSNP:rs2305479 and dbSNP:rs2305480) in linkage disequilibrium with a marker of disease risk (22). Based on the numbering scheme of the canonical GSDMB (Uniprot Q8TAX9-1), the rs230549 polymorphism corresponds to a Gly-to-Arg change at position 299, and the rs2305480 polymorphism corresponds to a Pro-to-Ser change at position 306 in the C-terminal domain of GSDMB (GSDMB_C).…”

“…Based on the numbering scheme of the canonical GSDMB (Uniprot Q8TAX9-1), the rs230549 polymorphism corresponds to a Gly-to-Arg change at position 299, and the rs2305480 polymorphism corresponds to a Pro-to-Ser change at position 306 in the C-terminal domain of GSDMB (GSDMB_C). Further analyses of data compiled by the 1000 Genomes Project Consortium (33) showed that both versions of each SNP (Gly299:Pro306 or Arg299:Ser306) is common in the population and that the two SNPs cooccur in ∼95% of the genomes (22). We have determined three crystal structures of the GSDMB_C domain containing the Arg299:Ser306 sequence encoded by the allele linked to increased risk of complex-trait inflammatory diseases, the Gly299:Pro306 sequence encoded by the alternative allele, and the Gly299:Ser306 sequence that corresponds to one residue from each allele.…”

“…The overexpression of GSDMC in metastatic melanoma cells is an exception to its apoptotic role (9). In addition to cancer, genome-wide association studies (GWAS) have revealed a correlation between single nucleotide polymorphisms (SNPs) in both the protein coding and transcriptional regulatory regions of the neighboring genes GSDMA, GSDMB, and ORDML3 in the 17q12.2.1 loci and susceptibility to diseases such as asthma (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), type 1 diabetes (21,22), Crohn's disease, ulcerative colitis (22,23), and rheumatoid arteritis (22,24). The mechanisms by which these SNPs affect susceptibility to developing complex-trait inflammatory diseases are unknown.…”

The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog)

“…(8); for evidence of pleiotropy by Sivakumaran et al . (9); for loci associated with seven common diseases to identify possible causal missense variants by Pal and Moult, 2015 (10); and for identification of new targets for known drugs by Mullen et al . (11).…”